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Study of the neuronal molecular mechanisms in TAU uptake

Boek - Dissertatie

Tauopathies are a form of neurodegenerative disorders, that include Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), characterized by the deposition of hyperphosphorylated Tau aggregates under the form of neurofibrillary tangles (NFTs)(Goedert et al. 1988; Kosik et al 1986). Under normal conditions, Tau is a highly soluble cytoplasmic protein expressed predominantly in neurons, responsible for binding and stabilizing microtubules (Drechsel et al. 1992). Studies indicate that the NFT load strongly correlates with the clinical picture in AD patients (Arriagada et al. 1992; Heiko Braak et al. 2011). Furthermore, point mutations in the Tau encoding MAPT gene have been shown to cause FTLD with pathological Tau inclusions (Hutton et al. 1998; Combs and Gamblin 2013). Therefore it is widely accepted that Tau is a pathogenic player in AD and other tauopathies. In AD, tau pathology develops in a typical temporospatial pattern indicative of transsynaptic propagation. NFTs are first observed in the locus coeruleus, after which they propagate to the hippocampus and neocortex via the entorhinal cortex, leading to cell death and disease progression. The progressive loss of neurons in specific areas of the central nervous system is correlated with abnormal deposition of Tau aggregates (H Braak and Braak 1991). Temporospatial spreading of pathology is a common feature of many neurodegenerative disorders, including Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) or prion disease (Medina and Avila 2014). The transsynaptic propagation of pathology in these neurodegenerative disorders requires release of the pathological protein species from the donor neuron and subsequent uptake by the receiving neuron. Indeed recent in vitro and in vivo studies have shown that pathological protein species related to each of these disorders such as tau in AD, α-synuclein in PD or huntingtin in HD, are being released and capable of entering into neighboring cells. There, such pathological protein species can function as nuclei alias seeds that recruit non-pathological monomers to aggregate, thus stimulating the spreading or propagation of the pathology (Figure 2) (Clavaguera et al. 2015). The molecular mechanisms underlying the propagation of the different pathological protein species is a topic of intense research and with respect to Tau propagation the central theme of this research proposal. Protein seeds can be released into the extracellular space in a free form or within membrane-bound vesicles, such as exosomes. Free seeds may directly penetrate the plasma membrane of a recipient neuron or enter the neuron by fluid-phase or receptor-mediated endocytosis. Exosomes containing seeds may fuse with the plasma membrane of a recipient neuron. The intercellular transfer of seeds may also occur through nanotubes that connect the cytoplasm of 2 adjoining cells. In the cytoplasm of recipient cells, seeds will grow into fibrils through the addition of protein monomers (Goedert et al 2014). The current proposal is an integral part of our efforts at Janssen to develop a disease modifying strategy for Alzheimer´s Disease, targeting Tau pathology. With this project we would like to gain further insight into the molecular mechanisms involved in the propagation of Tau pathology with the ultimate goal to modulate such propagation via inhibition of seed uptake or stimulation of seed clearance. To this end both in vitro and in vivo models of Tau propagation have been developed that were instrumental to prove transsynaptic Tau propagation and will be essential to the success of this project (Calafate et al 2015, Peeraer et al 2015, Stancu 2015).
Jaar van publicatie:2021
Toegankelijkheid:Open